1. ¹Department of Gastroenterology, Graduate School of Medicinal Sciences, Kanazawa University, Kanazawa, Japan
2. ²Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
3. ³Division of Environmental Science, Forensic and Social Environmental Medicine, Graduate School of Medicinal Sciences, Kanazawa University, Kanazawa, Japan

Correspondence: Dr. Naofumi Mukaida, Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, Takara-machi 13-1, Kanazawa 920-0934, Japan. E-mail: naofumim@kenroku.kanazawa-u.ac.jp

Received 16 January 2002.

Abstract

TNF- has pleiotropic functions, but its role in liver fibrosis has not yet been clarified. To understand the pathophysiologic role of the TNF-/TNF receptor (TNFR) p55 signals in liver fibrosis, 10 mg/kg of dimethylnitrosamine, a specific hepatotoxicant, was administered twice a week into the peritoneal cavity of both TNFRp55 knock-out (KO) and wild-type mice, and the severity of fibrosis was monitored histologically and biochemically. In wild-type mice, histologic analysis demonstrated evident fibrotic changes 1 week after the initiation of dimethylnitrosamine administration, consistent with increased liver collagen contents. Concomitantly, the numbers of Kupffer cells and activated hepatic stellate cells (HSCs) were increased in liver tissue. On the contrary, fibrotic changes were attenuated and the numbers of Kupffer cells and HSCs were decreased in TNFRp55-KO mice. Moreover, gene expression of TNF- and monocyte chemoattractant protein-1, which are involved in Kupffer cell activation or migration, was decreased in the liver of TNFRp55-KO mice. Collectively, TNFRp55-mediated signals may regulate activation of Kupffer cells and HSCs and eventually enhance fibrotic process.